Abstract

Background

Although the ALK inhibitor (ALKi) crizotinib (CRZ) achieves high responses in pts with ALK+ NSCLC, disease progression within 1 year often occurs, with the brain/central nervous system (CNS) as a common site of progression and relapse. Ceritinib is a novel oral ALKi with 20-fold greater potency than CRZ in enzymatic assays that crosses the blood-brain barrier with good CNS penetration in preclinical studies. In the pivotal phase I study (NCT01283516), ceritinib was highly active in ALK+ NSCLC pts (regardless of prior CRZ exposure) and achieved intracranial responses in 7 of 14 pts with measurable baseline brain lesions. The adverse events profile in these pts was similar to that of the full study population.

Trial design

This international prospective phase II open-label study is designed to evaluate the antitumor activity of ceritinib in pts with ALK+ NSCLC metastatic to the brain or leptomeninges (ASCEND-7; CLDK378A2205). Eligible pts must have centrally assessed ALK+ NSCLC metastatic to the brain and ≥1 extracranial measurable lesion using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Pts must be neurologically stable ≥1 week prior to study drug and will be allocated to 1 of 5 cohorts depending on prior treatment:

ARMS 1-4 (pts w/active* brain mets, w/o LC)

Prior ALKi treatment

NO prior ALKi treatment

Prior whole brain radiotherapy (WBRT)

ARM 1

ARM 3

NO prior WBRT

ARM 2

ARM 4

ARM 5: pts with leptomeningeal carcinomatosis (LC) with or without evidence of active lesion at baseline

*Lesion free of local treatment (stereotactic or WBRT) or lesions in unequivocal progression after radiotherapy. Oral ceritinib 750 mg/day will be dosed on a continuous schedule and study assessments are consistent across cohorts. The primary and key secondary objectives are to evaluate whole body overall response rate and disease control rate, respectively. Other secondary objectives include assessment of intracranial and extracranial responses for all pts and for each cohort 1–4; overall survival and safety for all pts and for each cohort 1–5; and ceritinib pharmacokinetics in all pts. Enrolment is ongoing.

Clinical trial identification NCT02336451

Disclosure

L.Q. Chow: Consultant: Novartis. Funding Other: Research support (funds directly to University of Washington).